The Yale SPORE in Lung Cancer (YSILC) coalesces translational scientists spanning all aspects of cancer research to converge on the lung cancer problem. The YSILC leverages existing Yale Cancer Center (YCC) strengths including immunobiology, microRNA research, experience with anti-EGFR treatments with acquired resistance, and the behavioral interventions/biological underpinnings of smoking cessation. The goal of the YSILC program is to improve the overall survival rate of lung cancer patients by developing novel therapeutics and personalized prevention strategies based on an understanding of the targetable biochemical and immunological pathways involved in the progression of lung cancer and the acquisition of resistance to therapy. The YSILC translational research team will accomplish this objective through five specific aims: Specific Aim 1: Develop and test novel therapeutics by discovering the mechanisms underlying the response and resistance to anti-PD-1 and anti-B7- H1 (PD-L1) therapies; Specific Aim 2: Evaluate the potential of non-coding microRNAs as targeted therapies; Specific Aim 3: Understand and target the EGFR pathway in mutant/resistant lung cancer; Specific Aim 4: To develop and test the efficacy of a new personalized approach to gain-framed messaging to improve smoking cessation in Americans with asymptomatic lung nodules who continue to smoke; and Specific Aim 5: To develop new research directions and nurture the next generation of translational investigators in lung cancer through a Developmental Research Program and a Career Development Program. Three cores (Administrative; Biostatistics and Bioinformatics; and Biospecimen, Pathology, and Genomics) are proposed to support the projects and their clinical aims, mechanistic studies, and evaluation of biomarkers for clinical application. The highly coordinated YSILC projects, cores, and programs are focused on developing novel lung cancer therapies, with analysis of patient samples, cell-based assays, production of human cell lines and animal models of disease as a guide to design prospective trials that translate these innovative targeted approaches to clinical therapies. The expected translational outcomes of the program include: (1) A highly coordinated and focused development of novel lung cancer therapies; (2) an improved understanding of resistance pathways to PD-1/B7-H1 blockade and EGFR therapies, including prospective studies to overcome/prevent these effects; (3) an understanding of the therapeutic potential of miRNAs in patients; (4) development of effective smoking cessation methods while exploring correlative mechanistic markers; and (5) the development of the next generation of investigators.